Adipocyte-specific ablation of Gadd45b exacerbates obesity-associated cellular senescence and metabolic disorders via Fgf1b promoter hypermethylation

Cellular senescence contributes to obesity-associated adipose dysfunction, yet the upstream regulators of this process remain poorly understood. Here, we identified growth arrest and DNA damage-inducible protein 45 beta (Gadd45b) as an adaptive regulator of adipocyte senescence and systemic metabolic homeostasis. GADD45B expression was elevated in adipose tissue from obese human subjects and positively correlated with senescence-related markers. Adipocyte-specific Gadd45b deletion in mice caused depot-selective remodeling under high-fat diet, with inguinal fat hypertrophy but epididymal white adipose tissue (eWAT) atrophy, accompanied by enhanced DNA damage and pronounced senescence. These alterations thereby contributed to impaired lipolytic response, hepatic steatosis and insulin resistance, underscoring the vital role of Gadd45b in maintaining eWAT expandability during nutritional overload. Mechanistically, Gadd45b deficiency led to hypermethylation of fibroblast growth factor 1b (Fgf1b) promoter and reduced Fgf1 expression in eWAT, thereby exacerbating adipose senescence and metabolic abnormalities, while recombinant FGF1 treatment partially reversed these defects. Collectively, our findings establish Gadd45b as a depot-specific epigenetic regulator that sustains adipose tissue plasticity and links DNA damage responses to adipocyte senescence and metabolic homeostasis in obesity.